The increasing global energy demands and ensuing threat, be it accidental or intentional, of the release of nuclear material require a greater understanding of how to treat and mitigate radiation injury. While many studies describe the nature ofthe host response to radiation injury, established models provide very compelling evidence for a role for innate immunity in the process. Pathogen associated molecular patterns (PAMPs) released following gut injury stimulate tissue repair and host immune pathways. A recently described class of endogenous ligands released by injured cells, the damage associated molecular patterns (DAMPs), stimulate a similar group of innate immune receptors and so instigate a related program of tissue repair. These observations emphasize the point that very similar gene programs are involved in radiation repair and host immunity. The UCLA-CMCR has identified a number of different compounds and small molecules that are successful mitigators of radiation damage; the majority of which activate similar pathways as pathogens. From this comes the emerging understanding that a successful radiation mitigator suppresses excessive inflammation and supports robust regenerative gene programs leading to tissue repair. The optimal balance is exampled by lead compounds such as MIS416, an immune adjuvant that can successfully mediate crosstalk between Innate stimulation and radiation repair by regulating a number of signaling pathways. The same is true for other lead mitigators, such as IL-12, anti-inflammatory small molecules, or Tilorone, a type I interferon inducer. However, the molecular mechanisms responsible for mitigation remain unclear. In this application, we propose to discover which of the innate system pattern recognition receptors and which signal transduction pathways are required to support the mitigating activity of MIS416 and other UCLA-CMCR lead molecules. Furthermore, we will determine which genetic programs or cytokines contribute to the mitigating mechanism by inducing regeneration of hematopoietic stem cells. Thirdly, utilizing this increased understanding of the interaction between lead mitigators and innate immune regulatory systems, we shall develop a nanovesicle platform for radiation mitigation. Finally, we will examine a live vaccine model to explore the crosstalk between tissue repair mechanisms utilized in response to radiation injury and infection. Our proposed studies, by dissecting the receptors and pathways that mitigate radiation injury, will provide novel targets for therapeutic intervention and lead molecule verification. Our improved understanding of the similarities between responses activated by radiation and infection will drive design of additional novel strategies for intervention.